Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4858—Organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• the present disclosure relates to the field of medicine and the treatment of medical conditions associated with tuberous sclerosis complex. More specifically, the present disclosure relates to use of compositions comprising 2-chloro-4-[ 1 -(4-fluorophenyl)-2, 5-dimethyl- 1 H1 - imidazol-4-ylethynyl]pyridine, or a pharmaceutically acceptable salt thereof, in the treatment or amelioration of medical conditions associated with tuberous sclerosis complex.
• Tuberous sclerosis complex is a genetic disorder characterized by the growth of numerous noncancerous tumors in many parts of the body such as the skin, brain, kidneys, and other organs. TSC can cause developmental issues and in some cases lead to significant health problems. Typically, TSC results from mutations in the TSC1 or TSC2 gene, which codes for the proteins hamartin and tuberin, respectively, with TSC2 mutations accounting for the majority and tending to cause more severe symptoms.
• TSC tuberous sclerosis complex
• treating uses a composition comprising a crystalline anhydrate form (Form A) of a monosulfate salt of the compound of Formula I, wherein Form A has an X- ray powder diffraction (XRPD) pattern as substantially shown in FIG. 1.
• Form A is characterized by the following X-ray powder diffraction peaks obtained with a CU Ka radiation at 2Q (2 Theta): 9.8 ⁇ 0.2°, 13.4+0.2°, 14.2+0.2°, 18.1+0.2°, 18.9+0.2°, 19.6+0.2°, 22.6 ⁇ 0.2°, 22.9 ⁇ 0.2°, 25.7 ⁇ 0.2°, 27.1 ⁇ 0.2°, and 29.9 ⁇ 0.2°.
• the crystalline Form A typically has a T m of about 180-190 °C by differential scanning calorimetry (DSC) analysis.
• treating uses a composition comprising a crystalline monohydrate form (Form B) of a monosulfate salt of the compound of Formula I, wherein Form B has an XRPD pattern as substantially shown in FIG. 2.
• the crystalline Form B typically has a T m of about 60-70 °C by DSC analysis.
• treating uses a composition comprising a crystalline hemihydrate form (Form C) of a hemisulfate salt of the compound of Formula I, wherein Form C has an XRPD pattern as substantially shown in FIG. 3.
• the crystalline Form C typically has a T m of about 90-100 °C by DSC analysis.
• the composition used is a tablet formulation such as a modified release tablet formulation, or a matrix pellet formulation such as a modified release matrix pellet formulation, which can be encapsulated in a capsule, as defined herein.
• treating uses a composition comprising a pharmaceutically acceptable salt of the compound of Formula I, wherein said salt is 90% by weight or more (e.g., 95% by weight or more, or 99% by weight or more) in crystalline Form A based on the total weight of the salt present in the composition.
• the present disclosure also includes a solid pharmaceutical composition comprising a solid form of a compound of Formula I:
• the solid form is a crystalline anhydrate form (Form A) of a monosulfate salt of the compound of Formula I, characterized by at least three peaks selected from the following XRPD peaks obtained with a Cui 3 ⁇ 4 radiation at 2Q (2 Theta): 9.8 ⁇ 0.2°, 13.4 ⁇ 0.2°, 14.2 ⁇ 0.2°, 18.1 ⁇ 0.2°, 18.9+0.2°, 19.6+0.2°, 22.6 ⁇ 0.2°, 22.9 ⁇ 0.2°, 25.7 ⁇ 0.2°, 27.1+0.2°, and 29.9 ⁇ 0.2°; and has a median particle size (Dv50) of less than or equal to about 100 pm, wherein the solid pharmaceutical composition is the form of a matrix pellet.
• the solid form has a particle size of less than 47 pm (e.g., about 25 pm or less, or about 10 pm or less).
• the pharmaceutical composition comprises the Form A monosulfate salt characterized by the following XRPD peaks obtained with a CU Ka radiation at 2 ⁇ (2 Theta): 9.8 ⁇ 0.2°, 13.4+0.2°, 14.2+0.2°, 18.1+0.2°, 18.9+0.2°, 19.6+0.2°, 22.6 ⁇ 0.2°, 22.9 ⁇ 0.2°, 25.7 ⁇ 0.2°, 27.1+0.2°, and 29.9 ⁇ 0.2°.
• the pharmaceutical composition comprises the Form A monosulfate salt characterized by an XRPD pattern as substantially shown in FIG. 1.
• the present disclosure also includes a method of preparing a matrix pellet comprising a crystalline anhydrate form (Form A) of a monosulfate salt of a compound of Formula I: wherein the method comprises: granulating the Form A monosulfate salt and one or more polymers with purified water to form a mixture; extruding, spheronizing, drying, and sieving the mixture to afford a solid material; and blending the solid material with another pharmaceutical excipient to afford a matrix pellet.
• a method of preparing a matrix pellet comprising a crystalline anhydrate form (Form A) of a monosulfate salt of a compound of Formula I: wherein the method comprises: granulating the Form A monosulfate salt and one or more polymers with purified water to form a mixture; extruding, spheronizing, drying, and sieving the mixture to afford a solid material; and blending the solid material with another pharmaceutical excipient to afford a matrix pellet.
• the method of preparation further comprises filling the matrix pellet into a capsule to form a matrix pellet capsule.
• the one or more polymers are selected from the group consisting of a cellulose such as microcrystalline cellulose, methacrylic acid copolymer, and hypromellose.
• the other pharmaceutical excipient is talc.
• mGlu5 negative allosteric modulator NAM
• mGlu5 NAM is a compound of Formula I:
• FIG. 1 depicts an exemplary XRPD pattern of a crystalline anhydrate form (Form A) of a monosulfate of the compound of Formula I.
• FIG. 2 depicts an exemplary XRPD pattern of a crystalline monohydrate form (Form B) of a monosulfate of the compound of Formula I.
• FIG. 3 depicts an exemplary XRPD pattern of a crystalline hemihydrate form (Form C) of a hemisulfate of the compound of Formula I.
• the present disclosure provides methods of treating medical conditions associated with tuberous sclerosis complex (TSC) in a subject in need thereof.
• TSC tuberous sclerosis complex
• the present disclosure also describes treating medical conditions associated with TSC by using certain crystalline forms of pharmaceutically acceptable salts of the compound of Formula I.
• the present disclosure provides a solid form of a crystalline anhydrate form (Form A) of a monosulfate salt of the compound of Formula I, wherein the solid form has a particle size (Dv50) of less than or equal to about 100 pm (e.g., less than 47 pm, or 10 pm or less).
• Dv50 particle size
• compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
• variable or parameters are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,
• compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.
• composition or “pharmaceutical composition” or “pharmaceutical formulation” refers to the combination of an active agent with an excipient or a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
• “Pharmaceutically acceptable” refers to compounds, molecular entities, compositions, materials and/or dosage forms that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate, and/or that are approved or approvable by a regulatory agency of the federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
• “pharmaceutically acceptable salt” refers to any salt of an acidic or a basic group that may be present in a compound of the present invention (e.g., the compound of Formula I), which salt is compatible with pharmaceutical administration.
• acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene -p- sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acid.
• Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.
• bases include, but are not limited to, alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and compounds of formula NW 4 + , wherein W is C 1-4 alkyl, and the like.
• alkali metal e.g., sodium and potassium
• alkaline earth metal e.g., magnesium and calcium
• W is C 1-4 alkyl
• salts include, but are not limited, to acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, monosulfate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate
• salts include anions of the compounds of the present invention compounded with a suitable cation such as Na + , K + , Ca 2+ , NHC, and NWC (where W can be a C 1-4 alkyl group), and the like.
• salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable.
• salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
• pharmaceutically acceptable excipient refers to a substance that aids the administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient.
• Non-limiting examples of pharmaceutically acceptable excipients include water, NaC1, normal saline solutions, such as a phosphate buffered saline solution, emulsions (e.g., such as an oil/water or water/oil emulsions), lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
• normal saline solutions such as a phosphate buffered saline solution
• emulsions e.g., such as an oil/water or water/oil emulsions
• lactated Ringer’s normal sucrose, normal glucose, binders, fillers, disintegrants, lub
• Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
• auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
• auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
• a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non- human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
• the subject is a human.
• the subject is a non-human animal.
• solid dosage form means a pharmaceutical dose(s) in solid form, e.g., tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers and chewables.
• administering means oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration, transmucosal administration (e.g., buccal, sublingual, nasal, or transdermal), or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject.
• Parenteral administration includes, e.g., intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
• Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
• co-administer it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g., anti-cancer agent, chemotherapeutic, or treatment for a neurodegenerative disease).
• additional therapies e.g., anti-cancer agent, chemotherapeutic, or treatment for a neurodegenerative disease.
• the compound of Formula I, or a pharmaceutically acceptable salt thereof can be administered alone or can be co-administered to the patient.
• Co-administration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent).
• the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).
• the terms “treat,” “treating” and “treatment” include an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (e.g., “therapeutic treatment”).
• “Treat,” “treating” and “treatment”, as used herein, can include any effect, for example, lessening, reducing, modulating, ameliorating, or eliminating, that results in the improvement of the condition, disease, disorder, and the like, including one or more symptoms thereof. Treating can be curing, improving, or at least partially ameliorating the disorder.
• terapéuticaally effective amount refers to the amount of a compound (e.g., a compound of Formula I), or a pharmaceutically acceptable salt thereof, that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
• the compound, or a pharmaceutically acceptable salt thereof, described in the present disclosure can be administered in therapeutically effective amounts to treat a disease.
• a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof can be the quantity required to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in lessening of a symptom of a disease such as TSC.
• Tuberous sclerosis complex is a rare, multi-system genetic disease that causes benign tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. TSC usually affects the central nervous system and results in a combination of symptoms including seizures, developmental delay, behavioral problems, skin abnormalities, and kidney disease. See e.g., https://www.ninds.nih.gov/Disorders/Patient-Caregiver- Education/Fact-Sheets/Tuberous-Sclerosis-Fact-Sheet.
• the compound of Formula I is an mGlu5 negative allosteric modulator (NAM), also known as 2-chloro-4-[l-(4-fluorophenyl)-2, 5-dimethyl- 1H -imidazol-4- ylethynyl]pyridine :
• NAM mGlu5 negative allosteric modulator
• the compound of Formula I as described herein includes crystalline solid forms of either the free base or pharmaceutically acceptable salts of the compound of Formula I as descrbied herein.
• the pharmaceutically acceptable salt of the compound of Formula I can be a salt of the compound of Formula I with physiologically compatible mineral acids, such as hydrochloric acid, sulfuric (or sulphuric) acid, sulphurous acid or phosphoric acid; or with organic acids, such as methanesulphonic acid, p-toluenesulphonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.
• An exemplary pharmaceutically acceptable salt of the compound of Formula I is a monosulfate salt or a hemisulfate salt.
• the pharmaceutically acceptable salt of the compound of Formula I is a monosulfate salt or a hemisulfate salt, each being in hydrate or anhydrate form (e.g., anhydrate, hemihydrate, or monohydrate).
• the pharmaceutically acceptable salt of the compound of Formula I is in a crystalline form or an amorphous form.
• the compound is in a crystalline anhydrate form (Form A) of a monosulfate salt of the compound of Formula I, wherein Form A has an X-ray powder diffraction (XRPD) pattern as substantially shown in FIG. 1.
• Form A is characterized by at least three peaks selected from the following X-ray powder diffraction peaks obtained with a CU Ka radiation at 2Q (2 Theta): 9.8 ⁇ 0.2°, 13.4 ⁇ 0.2°, 14.2 ⁇ 0.2°, 18.1 ⁇ 0.2°, 18.9 ⁇ 0.2°, 19.6 ⁇ 0.2°, 22.6 ⁇ 0.2°, 22.9 ⁇ 0.2°, 25.7 ⁇ 0.2°, 27.1+0.2°, and 29.9 ⁇ 0.2°.
• the crystalline Form A typically has a T m of about 180-190 °C by DSC analysis.
• Form A is characterized by an infrared spectrum having sharp bands at 3068, 2730, 2618, 2236, 2213,1628, 1587,1569, 1518, 1384,1374, 1295,1236, 1168, 1157, 1116, 1064, 1019, 902, 855, 786, and 674 cm -1 ( ⁇ 3 cm -1 ).
• the compound is in a crystalline monohydrate form (Form B) of a monosulfate salt of the compound of Formula I, wherein Form B has an XRPD pattern as substantially shown in FIG. 2.
• the crystalline Form B typically has a T m of about 60-70 °C by DSC analysis.
• the compound is in a crystalline hemihydrate form (Form C) of a hemisulfate salt of the compound of Formula I, wherein Form C has an XRPD pattern as substantially shown in FIG. 3.
• the crystalline Form C typically has a T m of about 90-100 °C by DSC analysis.
• the present disclosure relates to a composition such as a pharmaceutical composition comprising the compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, for the treatment of TSC in a subject in need thereof.
• the composition is a solid pharmaceutical composition.
• the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be from about 0.01 mg to about 30 mg, about 0.05 mg to about 20 mg, about 0.1 mg to about 10 mg, about 0.5 mg to about 10 mg, about 1 mg to about 10 mg, about 2 mg to about 10 mg, about 3 mg to about 10 mg, about 4 mg to about 10 mg, about 5 mg to about 10 mg, about 6 mg to about 10 mg, about 7 mg to about 10 mg, about 8 mg to about 10 mg, about 9 mg to about 10 mg, about 1 mg to about 9 mg, about 1 mg to about 8 mg, about 1 mg to about 7 mg, about 1 mg to about 6 mg, about 1 mg to about 5 mg, about 1 mg to about 4.5 mg, about 1 mg to about 4 mg, about 1 mg to about 3.5 mg, about 1 mg to about 3 mg, about 1 mg to about 2.5 mg, about 1 mg to about 2 mg, about 1 mg to about 1.5 mg, about 1.5 mg to about 9 mg, about 1.5 mg
• the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.
• the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be about 0.1 mg to about 0.2 mg (e.g., about 0.13 mg).
• the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be about 0.2 mg to about 0.3 mg (e.g., about 0.26 mg).
• the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be about 0.6 mg to about 0.7 mg (e.g., about 0.65 mg).
• the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be about 1.2 mg to about 1.4 mg (e.g., about 1.3 mg).
• the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be about 1 mg to about 4 mg. In certain embodiments, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be about 1 mg to about 3 mg. In certain embodiments, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be about 1.5 mg to about 4.5 mg. In certain embodiments, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be about 1.5 mg to about 3.5 mg.
• the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be about 3.5 mg, about 3.0 mg, about 2.5 mg, about 2.0 mg, about 1.5 mg, or about 1.0 mg. In certain embodiments, the amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be about 5.0 mg, about 4.5 mg, about 4.0 mg, about 3.5 mg, about 3.0 mg, about 2.5 mg, about 2.0 mg, about 1.5 mg, about 1.0 mg, or about 0.5 mg.
• the compound of Formula I, or a pharmaceutically acceptable salt thereof is present in the composition in an amount from about 0.01% to about 20% by weight, about 0.05% to about 15% by weight, about 0.1% to about 10% by weight, about 0.1% to about 5% by weight, about 0.1% to about 1% by weight, or about 0.1% to about 0.5% by weight, based on the total weight of the composition.
• the compound of Formula I, or a pharmaceutically acceptable salt thereof is present in the composition in an amount from about 0.05% to about 15% by weight.
• the compound of Formula I, or a pharmaceutically acceptable salt thereof is present in the composition in an amount from about 0.1% to about 0.5% by weight.
• the pharmaceutical compositions described herein comprise a therapeutically effective amount of a pharmaceutically acceptable salt of the compound of Formula I.
• the pharmaceutically acceptable salt of the compound of Formula I can be a salt of the compound of Formula I with physiologically compatible mineral acids, such as hydrochloric acid, sulfuric acid, sulphurous acid or phosphoric acid; or with organic acids, such as methanesulphonic acid, p-toluenesulphonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.
• physiologically compatible mineral acids such as hydrochloric acid, sulfuric acid, sulphurous acid or phosphoric acid
• organic acids such as methanesulphonic acid, p-toluenesulphonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.
• the pharmaceutically acceptable salt of the compound of Formula I is a monosulfate salt or a hemisulfate salt, each being in hydrate or anhydrate form (e.g., anhydrate, hemihydrate, or monohydrate).
• the pharmaceutically acceptable salt of the compound of Formula I is in a crystalline form or an amorphous form.
• the pharmaceutical compositions described herein comprise a crystalline anhydrate form (Form A) of a monosulfate salt of the compound of Formula I, wherein Form A has an X-ray powder diffraction (XRPD) pattern as substantially shown in FIG. 1.
• the crystalline Form A typically has a T m of about 180-190 °C by DSC analysis (e.g., 180 ⁇ 1 °C, 182 ⁇ 1 °C, 184 ⁇ 1 °C, 186 ⁇ 1 °C, 188 ⁇ 1 °C, or 190 ⁇ 1 °C).
• the pharmaceutical compositions described herein comprise a crystalline monohydrate form (Form B) of a monosulfate salt of the compound of Formula I, wherein Form B has an XRPD pattern as substantially shown in FIG. 2.
• the crystalline Form B typically has a T m of about 60-70 °C by DSC analysis (e.g., 60 ⁇ 1 °C, 62 ⁇ 1 °C, 64 ⁇ 1 °C,
• the pharmaceutical compositions described herein comprise a crystalline hemihydrate form (Form C) of a hemisulfate salt of the compound of Formula I, wherein Form C has an XRPD pattern as substantially shown in FIG. 3.
• the crystalline Form C typically has a T m of about 90-100 °C by DSC analysis (e.g., 90 ⁇ 1 °C, 92 ⁇ 1 °C, 94 ⁇ 1 °C,
• the pharmaceutical compositions described herein comprise an amorphous form of a monosulfate salt of the compound of Formula I, wherein said amorphous form is characterized by an infrared spectrum having bands at 2730, 2592, 2219, 1633, 1586, 1570, 1513, 1375, 1343, 1293, 1226, 1157, 1130, 1084, 1040, 986, 903, 848, 788, 712 and 670 cm -1 ( ⁇ 3 cm -1 ).
• the pharmaceutical composition is a tablet formulation such as a modified release tablet formulation, or a matrix pellet formulation such as a modified release matrix pellet formulation, which can be encapsulated in a capsule.
• a “modified release formulation,” or a “modified-release dosage,” as used herein, refers to a mechanism that (in contrast to immediate-release dosage) delivers a drug with a delay after its administration (delayed-release dosage), or for a prolonged period of time (extended-release dosage). See, Perrie et al., Pharmaceutics: Drug Delivery and Targeting (2 nd ), 2012, 7-13.
• the pharmaceutical composition is a modified release matrix pellet formulation encapsulated in a capsule, wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is present in an amount from about 0.05 mg to about 20 mg (e.g., about 0.1 mg to about 0.2 mg, about 0.2 mg to about 0.3 mg, about 0.6 mg to about 0.7 mg, or about 1.2 mg to about 1.4 mg).
• the pharmaceutical composition is a modified release pellet formulation encapsulated in a capsule, wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is present in the composition in an amount from about 0.01% to about 20% by weight (e.g., about 0.05% to about 15% by weight, about 0.1% to about 1% by weight, or about 0.1% to about 0.5% by weight), based on the total weight of the composition.
• the pharmaceutical composition described herein comprises a crystalline anhydrate form (Form A) of a monosulfate salt of the compound of Formula I, wherein Form A has an XRPD pattern as substantially shown in FIG. 1 ; and the Form A monosulfate salt is present in the composition in an amount from about 0.05 mg to about 20 mg (e.g., about 0.1 mg to about 0.2 mg, about 0.2 mg to about 0.3 mg, about 0.6 mg to about 0.7 mg, or about 1.2 mg to about 1.4 mg).
• Form A crystalline anhydrate form
• the pharmaceutical composition described herein comprises a crystalline anhydrate form (Form A) of a monosulfate salt of the compound of Formula I, wherein Form A has an XRPD pattern as substantially shown in FIG. 1 ; and the Form A monosulfate salt is present in the composition in an amount from about 0.01 % to about 20% by weight (e.g., about 0.05% to about 15% by weight, about 0.1% to about 1% by weight, or about 0.1% to about 0.5% by weight), based on the total weight of the composition.
• Form A crystalline anhydrate form
• the present disclosure includes a solid pharmaceutical composition
• a solid pharmaceutical composition comprising a solid form of a compound of Formula I, namely, a crystalline anhydrate form (Form A) of a monosulfate salt of the compound of Formula I; where the composition is in the form of a matrix pellet and the solid form has a mean particle size (Dv50) of less than or equal to about 100 pm.
• the Dv50 can be determined by a LA-950 laser diffraction method.
• the pharmaceutical composition comprises a matrix pellet of the solid form having a particle size of less than 47 pm, less than 45 pm, less than 40 pm, less than 35 pm, less than 30 pm, less than 25 pm, less than 20 pm, less than 15 pm, less than 10 pm, or less than 5 pm.
• the solid form has a particle size of about 10 pm or less (e.g., about 10 pm, about 9 pm, about 8 pm, about 7 pm, about 6 pm, about 5 pm, about 4 pm, about 3 pm, about 2 pm, or about 1 pm).
• the solid form has a particle size of less than 47 pm and the Form A monosulfate salt is present in the composition in an amount of 1% by weight or less, based on the total weight of the composition.
• the solid form has a particle size of about 10 pm or less (e.g., about 3.3 pm), and the Form A monosulfate salt is present in the composition in an amount of 0.5% by weight or less (e.g., 0.1% by weight), based on the total weight of the composition.
• the pharmaceutical composition comprises comprises a pharmaceutical excipient comprising a polymer, a binder, a disintegrant, a lubricant, or a glidant.
• the polymer is a matrix forming polymer (e.g., microcrystalline cellulose), a pH-responding polymer (e.g., methacrylic acid copolymer), or a binder (e.g., hypromellose).
• the polymer is one or more polymers selected from the group consisting of a cellulose such as microcrystalline cellulose, methacrylic acid copolymer, and hypromellose.
• the glidant is talc.
• compositions provided herein can be administered by a variety of routes including, but not limited to, oral administration, administration as a suppository, topical contact, parenteral administration (e.g., intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial), intralesional administration, intrathecal administration, intranasal administration, transmucosal administration (e.g., buccal, sublingual, nasal, or transdermal), or the implantation of a slow-release device, e.g., a mini- osmotic pump, to a subject.
• the pharmaceutical compositions disclosed herein are administered orally.
• the pharmaceutical compositions provided herein may also be administered chronically (“chronic administration”).
• Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be continued indefinitely, for example, for the rest of the subject’s life.
• the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.
• the pharmaceutical compositions provided herein may be presented in unit dosage forms to facilitate accurate dosing.
• unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
• the pharmaceutical dosage forms described herein can be administered as a unit dose.
• Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
• the pharmaceutical compositions provided herein are administered to the patient as a solid dosage form.
• the solid dosage form is a capsule (e.g., a modified release pellet formulation encapsulated in a capsule).
• the solid dosage form is a tablet (e.g., a modified release tablet formulation).
• the pharmaceutical compositions provided herein comprise the compound of Formula I as the sole active agent, or in combination with other active agents.
• the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts.
• compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.
• General considerations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21 st ed., Lippincott Williams & Wilkins, 2005.
• TSC tuberous sclerosis complex
• kits for treating a medical condition associated with TSC in a subject in need thereof comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula I:
• mGlu5 negative allosteric modulator NAM
• mGlu5 NAM is a compound of Formula I:
• administering comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount of about 1.5 mg to about 3.5 mg once daily.
• the subject has a weight of at least 40 kg. In some embodiments, the subject has a weight of less than 40 kg.
• mGlu5 negative allosteric modulator NAM
• mGlu5 NAM is a compound of Formula I:
• administering comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount of about 1.0 mg to about 3.0 mg once daily.
• the subject has a weight of at least 40 kg. In some embodiments, the subject has a weight of less than 40 kg.
• administering a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof comprises administering to a subject from about 0.05 mg to about 20 mg (e.g., about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg) of the compound of Formula I, or a pharmaceutically acceptable salt thereof.
• about 0.05 mg to about 20 mg e.g., about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg,
• administering a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof comprises administering from about 0.1 mg to about 1.5 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• administering a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof comprises administering from about 0.1 mg to about 4 mg (e.g., from about 0.1 mg to about 3.8 mg, from about 0.1 mg to about 3.6 mg, from about 0.1 mg to about 3.4 mg, from about 0.1 mg to about 3.2 mg, from about 0.1 mg to about 3.0 mg, from about 0.1 mg to about 2.8 mg, from about 0.1 to about 2.6 mg, from about 0.1 mg to about 2.4 mg, from about 0.1 mg to about 2.2 mg, from about 0.1 mg to about 2.0 mg, from about 0.1 mg to about 1.8 mg, from about 0.1 mg to about 1.6 mg, from about 0.1 mg to about 1.4 mg, from about 0.1 mg to about 1.2 mg, from about 0.1 mg to about 1.0 mg, from about 0.1 mg to about 0.8 mg, from about 0.1 mg to about 0.6 mg, from about 0.1 mg to about 0.4 mg, from about 0.1 mg to about 0.1 mg to about 4 mg (e.
• administering is once daily.
• administering a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof comprises administering from about 0.1 mg to about 3 mg (e.g., about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, or about 3.0 mg) of the compound of Formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• the administering is once daily.
• administering a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof comprises administering from about 0.1 mg to about 3.5 mg (e.g., about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about
• the administering is once daily.
• administering a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof comprises administering about 1.0 mg to about 5.0 mg (e.g., about 1.0 mg to about 4.9 mg, about 1.0 mg to about 4.8 mg, about 1.0 mg to about 4.7 mg, about 1.0 mg to about 4.6 mg, about 1.0 mg to about 4.5 mg, about 1.0 mg to about 4.4 mg, about 1.0 mg to about 4.3 mg, about 1.0 mg to about 4.2 mg, about 1.0 mg to about 4.1 mg, about 1.0 mg to about 4.0 mg, about 1.0 mg to about 3.9 mg, about 1.0 mg to about 3.8 mg, about 1.0 mg to about 3.7 mg, and about 1.0 mg to about 3.6 mg) of the compound of Formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• about 1.0 mg to about 5.0 mg e.g., about 1.0 mg to about 4.9 mg, about 1.0 mg to about 4.8 mg, about 1.0 mg to about 4.7 mg, about
• administering a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof comprises administering about 1.0 mg to about 3.0 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In embodiments, administering a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, comprises administering about 0.5 mg to about 3.0 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• administering a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof comprises administering about 1.0 mg to about 3.5 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In embodiments, administering a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, comprises administering about 1.0 mg to about 4 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In various embodiments, the administering is once daily.
• administering a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof comprises administering about 1.5 mg to about 3.5 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In certain embodiments, the administering is once daily. In certain embodiments, administering a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, comprises administering about 1.5 mg to about 4.0 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In embodiments, the administering is once daily.
• administering a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof comprises administering about 1.5 mg to about 4.5 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In embodiments, administering a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, comprises administering about 1.0 mg to about 3.5 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In embodiments, administering a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, comprises administering about 0.5 mg to about 3.5 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In various embodiments, the administering is once daily.
• administering a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof comprises administering about about 3.5 mg, about 3.0 mg, about 2.5 mg, about 2.0 mg, about 1.5 mg, or about 1.0 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In certain embodiments, the administering is once daily.
• administering a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof comprises administering about about 6.0 mg, 5.5 mg, 5.0 mg, 4.5 mg, 4.0 mg, 3.5 mg, about 3.0 mg, about 2.5 mg, about 2.0 mg, about 1.5 mg, about 1.0 mg, or about 0.5 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• the administering is once daily.
• administering a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof comprises administering once daily about 3 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• the subject has a weight less than 40 kg. In certain embodiments, administering a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, comprises administering once daily about 3.5 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the subject has a weight less than 40 kg. In certain embodiments, administering a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, comprises administering once daily about 4.0 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• the subject has a weight less than about 40 kg. In some embodiments, the subject has a weight equal to or more than about 40 kg (e.g., about 40 kg, about 45 kg, about 50 kg, about 55 kg, about 60 kg, about 65 kg, about 70 kg, about 75 kg, about 80 kg, about 85 kg, about 90 kg, about 95 kg, about 100 kg, about 105 kg, about 110 kg, about 115 kg, about 120 kg, about 125 kg, about 130 kg, about 135 kg, about 140 kg, about 145 kg).
• about 40 kg, about 45 kg, about 50 kg, about 55 kg, about 60 kg, about 65 kg, about 70 kg, about 75 kg, about 80 kg, about 85 kg, about 90 kg, about 95 kg, about 100 kg, about 105 kg, about 110 kg, about 115 kg, about 120 kg, about 125 kg, about 130 kg, about 135 kg, about 140 kg, about 145 kg e.g., about 40 kg, about 45 kg, about 50 kg, about 55 kg, about 60 kg, about 65 kg,
• the subject weighs at least about 40 kg (e.g., about 38 kg, about 36 kg, about 34 kg, about 32 kg, about 30 kg, about 28 kg, about 26 kg, about 24 kg, about 22 kg, about 20 kg, about 18 kg, about 16 kg, about 14 kg, about 12 kg, about 10 kg, about 8 kg, about 6 kg, about 4 kg, about 2 kg).
• the subject has a weight of about 1 kg to about 40 kg (e.g., about 5 kg to about 40 kg, about 10 kg to about 40 kg, about 15 kg to about 40 kg, about 20 kg to about 40 kg, about 25 kg to about 40 kg, about 30 kg to about 40 kg, about 35 kg to about 40 kg).
• the subject has a weight of about 41 kg to about 100 kg (about 40 kg to about 100 kg, about 45 kg to about 100 kg, about 50 kg to about 100 kg, about 55 kg to about 100 kg, about 60 kg to about 100 kg, about 40 kg to about 45 kg, about 40 kg to about 50 kg, about 40 kg to about 55 kg, about 40 kg to about 60 kg, about 40 kg to about 65 kg, about 40 kg to about 70 kg, about 40 kg to about 80 kg, about 40 kg to about 90 kg).
• the subject weighs at least about 35 kg, about 30 kg, about 25 kg, about 20 kg, about 15 kg, about 10 kg, or about 5 kg.
• provided herein is a method of administering the free base form of the compound of Formula I for the treatment of medical conditions associated with TSC in a subject in need thereof.
• provided herein is a method of administering a pharmaceutically acceptable salt of the compound of Formula I for the treatment of medical conditions associated with TSC in a subject in need thereof.
• treating comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, once, twice, three, four, or five times daily. In certain embodiments, treating comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, once daily.
• treating comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, by a variety of routes including, but not limited to, oral administration, administration as a suppository, topical contact, parenteral administration (e.g., intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial), intralesional administration, intrathecal administration, intranasal administration, transmucosal administration (e.g., buccal, sublingual, nasal, or transdermal), or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject.
• parenteral administration e.g., intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial
• intralesional administration e.g., intrathecal administration, intranasal administration, transmucosal administration (e.g., buccal, sub
• treating comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, by oral administration.
• treating comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof, as a unit dose.
• treating comprises administering the compound of Formula I as the free base form.
• treating comprises administering the compound of Formula I in the form of a pharmaceutically acceptable salt thereof.
• the pharmaceutically acceptable salt of the compound of Formula I can be a salt of the compound of Formula I with physiologically compatible mineral acids, such as hydrochloric acid, sulfuric (or sulphuric) acid, sulphurous acid or phosphoric acid; or with organic acids, such as methanesulphonic acid, p-toluenesulphonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.
• physiologically compatible mineral acids such as hydrochloric acid, sulfuric (or sulphuric) acid, sulphurous acid or phosphoric acid
• organic acids such as methanesulphonic acid, p-toluenesulphonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tarta
• treating comprises administering the compound of Formula I in a crystalline form (e.g., Form A, Form B, or Form C) in a sulfate salt form (e.g., a monosulfate salt or a hemisulfate salt).
• a crystalline form e.g., Form A, Form B, or Form C
• a sulfate salt form e.g., a monosulfate salt or a hemisulfate salt.
• mGlu5 negative allosteric modulator NAM
• mGlu5 NAM is a compound of Formula I:
• treating comprises administering the compound of Formula I as a monotherapy.
• the methods provided herein further comprise administering a therapeutically effective amount of another therapeutic agent to the subject.
• the present invention relates to use of the compound of Formula I, or a pharmaceutically acceptable salt thereof, for treating a medical condition (e.g., a disease or a disorder) associated with TSC.
• a medical condition e.g., a disease or a disorder
• the medical condition associated with TSC is a TSC-associated neuropsychiatric disorder, a TSC-associated tumor, or heart arrhythmia.
• the medical condition associated with TSC is a TSC-associated neuropsychiatric disorder selected from the group consisting of autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), anxiety disorder, and depressive disorder.
• the medical condition associated with TSC is a TSC-associated tumor selected from the group consisting of subependymal giant cell astrocytomas (SEGAs), angiomyolipomas (ALM), renal cell carcinoma, oncocytomas, lymphangioleiomyomatosis (LAM), cardiac rhabdomyomas, ungual fibromas, intraoral fibromas, retinal lesions, retinal hamartomas, and pancreatic neuroendocrine kidney diseases.
• SEGAs subependymal giant cell astrocytomas
• ALM angiomyolipomas
• LAM lymphangioleiomyomatosis
• cardiac rhabdomyomas ungual fibromas
• intraoral fibromas intraoral fibromas
• retinal lesions retinal lesions
• retinal hamartomas pancreatic neuroendocrine kidney diseases.
• the medical condition associated with TSC is selected from the group consisting of seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, lung diseases, kidney diseases, and heart diseases.
• the therapeutic effect of the treatment is determined by: a) reduction of seizure occurrence; b) reduction of the size of a tumor in the brain, eyes, heart, kidney, skin, or lungs; c) suppression of tumor growth in the brain, eyes, heart, kidney, skin, or lungs; or d) improvement of cognitive function.
• the efficacy of the compound is determined by Caregiver Global Impression of Change. In some embodiments, the efficacy of the compound is determined by Sheehan disability scale. In some embodiments, the efficacy of the compound is determined by Patient Self-recorded Seizures.
• Example 1 Synthesis of 2-chloro-4-[l-(4-fluorophenyl)-2,5-dimethyl-lH-imidazol-4- ylethynyl]pyridine (Compound of Formula I, supra ) [See U.S. Patent No. 7,332,510].
• Form A monosulfate salt 61.0 g of2-chloro-4-[l-(4-fluoro-phenyl)-2,5-dimethyl-1H- imidazol-4-ylethynyl] -pyridine was dissolved in 610 mL of 2-propanol. The solution was filtered and the filter rinsed with 31 mL of 2-propanol. To the combined solutions a mixture of 30 mL of water and 18.91 g of sulfuric acid (97%) was added drop-wise. The solution was cooled to 0-5 °C. Seeding was performed at 58 °C as needed.
• Form A seeding crystals can be prepared upon cooling crystallization of a hot solution of 250 mg of the monosulfate salt in 10 mL of 2-propanol. After cooling to 0 °C, the solid residues can be filtered and dried at 50 °C under vacuum to afford Form A monosulfate salt, which was confirmed by the XRPD pattern as substantially shown in FIG. 1.
• Form B monosulfate salt 300 mg of Form A monosulfate salt of the compound of Formula I was dissolved in 3 mL 2-propanol and 1 mL water at 60 °C to produce a clear solution. The clear solution was seeded with Form B monosulfate salt and sealed at room temperature (e.g., about 25 °C). Single crystals were formed after 3 days. Seeding crystals can be prepared by formation of a saturated slurry of Form A monosulfate salt of the compound of Formula I in 2-propanol and water (3: 1 v/v) at room temperature. The slurry was stirred at room temperature for approximately 3 weeks.
• Form C hemisulfate salt 41 g of Form A monosulfate of the compound of Formula I was mixed with 128 g of water. The slurry was stirred at room temperature for 2-16 hrs. After all the Form A monosulfate salt had been converted to the hemisulfate salt, the resulting crystals were collected by filtration and rinsed with water. The wet cake thus obtained was dried at 40 °C in a vacuum oven for 48 hrs to afford Form C hemisulfate salt in a yield of 93%. Form C hemisulfate salt was confirmed by the XRPD pattern as substantially shown in FIG. 3.
• Amorphous monosulfate salt 0.53 g of a monosulfate of the compound of Formula I was dissolved in 10 mL of methanol at approximately 65 °C. After complete evaporation of the solvent under vacuum, the solid (foam) was further dried at about 50 °C under 5-20 mbar for 18 hrs. Analysis (XRPD and DSC) revealed amorphous form of the compound of Formula I was obtained.
• the amorphous monosulfate salt was characterized by an infrared spectrum having bands at 2730, 2592, 2219, 1633, 1586, 1570, 1513, 1375, 1343, 1293, 1226, 1157, 1130, 1084, 1040, 986, 903, 848, 788, 712 and 670 cm -1 ( ⁇ 3 cm -1 ).
• the glass transition temperature (T g ) of the amorphous form determined by DSC was largely dependent on the solvent content and was observed for the wet sample (closed pan) at about 42 °C and for the in-situ dried sample (pan with perforation lid) at about 77 °C.
• matrix pellets Two different matrix pellet compositions were prepared according to the formulations shown in Table 1 below.
• the matrix pellets thus obtained were filled into capsules to afford matrix pellet capsules.
• Step 3 Transfered all the materials from Step 2 into a high shear granulator followed by the mixture from Step 1. Mix all the components for two minutes using the impeller and chopper at the following speeds: Impeller: 300 + 100 rpm and Chopper: 1500 + 500 rpm.
• Step 9 Placed the pellets from Step 9 in a bin blender or an equivalent, added talc and mixed for 5 minutes at 20 + 5 rpm.
• Step 11 Stored the filled capsules from Step 11 in double polyethylene-lined bags with two silica gel bags between the polyethylene bags in a closed fiber drum at a temperature not above 25 °C.
• matrix pellets prepared using API with Dv50 of 3.3 pm, 10 pm, and 47 pm exhibited USP uniformity of dosage units (UDU) acceptance value (AV) of 2.2, 6.3, 3.4, respectively, all meeting the UDU acceptance criteria (AV ⁇ 15).
• UDU dosage units
• AV dosage units
• matrix pellets prepared using API with Dv50 of 47 pm failed to meet the UDU acceptance criteria with an AV of 20.9; unexpectedly, matrix pellets prepared using API with Dv50 of 3.3 pm and 10 pm met the UDU acceptance criteria with an AV of 6.0 and 10.3, respectively.
• API particle size (Dv50) of 10 pm or less was shown to provide matrix pellets drug product with acceptable manufacturing process and drug product performance (e.g., content uniformity, pellet size distribution, and dissolution), thus more suitable for pharmaceutical durg development.
• Example 4 A Study of the Compound of Formula I for Treatment of Subjects with Tuberous Sclerosis Complex (TSC)
• TSC Tuberous Sclerosis Complex
• a Phase 2B, multicenter, 30-week, prospective, cross-over, double-blind randomized, placebo-controlled study is carried out, as shown in Table 2 and description below, to evaluate the efficacy and safety of daily 1.0 mg to 3.0 mg or 1.5 mg to 3.5 mg of the compound of Formula I (“CF-I”) adjunctive to ongoing epilepsy therapy in 55 patients with TSC who received a suboptimal response to their current anti-seizure therapy.
• CF-I compound of Formula I
• the study is done on pateitns with TSC who, despite optimal treatment with antiseizure therapies, show persistence of at least one type of focal or generalized seizure, including absences, drop seizures (atonic, tonic, tonic-clonic or myoclonic) for at least six months prior to study entry.
• Basimglurant dosing follows two weight categories ( ⁇ 40 kg and >40 kg).
• the initial dose of basimglurant is 1.0 mg once daily for patients weighing ⁇ 40 kg, and 1.5 mg once daily for patients weighing >40 kg.
• the maximum doses of basimglurant are 3.0 mg once daily for patients ⁇ 40 kg, and 3.5 mg once daily for patients >40 kg.
• the dose of basimglurant is escalated in a blinded fashion in 0.5 mg increments at weekly intervals according to individual tolerability. Once the dose escalation phase is completed, patients continue to receive the same dose of basimglurant throughout the maintenance phase.
• Part A comprises 4 periods.
• Period 1 is stabilization period (baseline) is 4 weeks. During this period, patients receive placebo and patients are monitored to ensure stability of their previous antiepileptic medications and to accurately record the frequency and duration of their seizures.
• Period 2 is 12 weeks double-blind treatment (study weeks 5 to 16). During this period, patients are randomized to basimglurant or placebo.
• Period 3 is 2 weeks washout (study weeks 17 and 18) of basimglurant, patients receive placebo.
• Period 4 is 12 weeks double-blind treatment (study weeks 19 to 30). During this period, patients who initially received placebo are assigned to receive basimglurant, and those who initially received basimglurant receive placebo.
• Basimglurant or matching placebo is administered once daily (preferably in the morning) with food for 12 weeks in Periods 2 and 4 (Weeks 5-16 and 19-30, respectively).
• Periods 2 and 4 Weeks 5-16 and 19-30, respectively.
• an initial 5-week dose escalation phase is followed by a 7-week maintenance phase.
• the investigator makes an overall assessment of the safety and tolerability of the current dose. Dose escalation only happen if the current dose is considered adequately tolerated, and the patient and their caregiver are in agreement. In the event of inadequate tolerability, patients can either continue on same dose or de-escalate by 0.5 mg at the discretion of the investigator.
• Part B comprises a 52-week OLE where all patients receives basimglurant. All OLE study participants restarts on basimglurant at the lowest dose according to their body weight, which are titrated to the maximum individually tolerated dose and are maintained on that dose until study end.
• Seizure frequency during study Periods 1-4 and the 52-week OLE period are monitored and recorded using patient/carer diaries and, if available at the time of study start, a wearable device that detects and records possible focal and generalized tonic-clonic seizures.

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